Dpp-iv inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation

ABSTRACT

The present invention relates to pharmaceutical compositions comprising fixed dose combinations of a DPP-4 inhibitor drug and a partner drug, processes for the preparation thereof, and their use to treat certain diseases.

The present invention relates to pharmaceutical compositions comprisingfixed dose combinations of a DPP-4 inhibitor drug and a partner drug,processes for the preparation thereof, and their use to treat certaindiseases.

In a more detailed aspect, the present invention relates to oral soliddosage forms for fixed dose combination (FDC) of a selected dipeptidylpeptidase-4 (DPP-4) inhibitor drug and a certain partner drug. The FDCformulations are chemically stable and either a) display similarity ofin-vitro dissolution profiles and/or are bioequivalent to the freecombination, or b) allow to adjust the in-vitro and in-vivo performanceto desired levels. In a preferred embodiment the invention relates tochemically stable FDC formulations maintaining the original dissolutionprofiles of corresponding mono tablets of each individual entity, with areasonable tablet size.

The enzyme DPP-4 also known as CD26 is a serine protease known to leadto the cleavage of a dipeptide from the N-terminal end of a number ofproteins having at their N-terminal end a prolin or alanin residue. Dueto this property DPP-4 inhibitors interfere with the plasma level ofbioactive peptides including the peptide GLP-1 and are considered to bepromising drugs for the treatment of diabetes mellitus.

For example, DPP-4 inhibitors and their uses are disclosed in WO2002/068420, WO 2004/018467, WO 2004/018468, WO 2004/018469, WO2004/041820, WO 2004/046148, WO 2005/051950, WO 2005/082906, WO2005/063750, WO 2005/085246, WO 2006/027204, WO 2006/029769 orWO2007/014886; or in WO 2004/050658, WO 2004/111051, WO 2005/058901, WO2005/097798; WO 2006/068163, WO 2007/071738, WO 2008/017670; WO2007/128721 or WO 2007/128761.

As further DPP-4 inhibitors the following compounds can be mentioned:

-   -   Sitagliptin (MK-0431) having the structural formula A below is        (3R)-3-amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one,        also named        (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine,

In one embodiment, sitagliptin is in the form of its dihydrogenphosphatesalt, i.e. sitagliptin phosphate. In a further embodiment, sitagliptinphosphate is in the form of a crystalline anhydrate or monohydrate. Aclass of this embodiment refers to sitagliptin phosphate monohydrate.Sitagliptin free base and pharmaceutically acceptable salts thereof aredisclosed in U.S. Pat. No. 6,699,871 and in Example 7 of WO 03/004498.Crystalline sitagliptin phosphate monohydrate is disclosed in WO2005/003135 and in WO 2007/050485.

For details, e.g. on a process to manufacture this compound or a saltthereof, reference is thus made to these documents.

-   -   Vildagliptin (LAF-237) having the structural formula B below is        (2S)-{[(3-hydroxyadamantan-1-yl)amino]acetyl}pyrrolidine-2-carbonitrile,        also named        (S)-1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyano-pyrrolidine,

Vildagliptin is specifically disclosed in U.S. Pat. No. 6,166,063 and inExample 1 of WO 00/34241. Specific salts of vildagliptin are disclosedin WO 2007/019255. A crystalline form of vildagliptin is disclosed in WO2006/078593. A crystalline form of vildagliptin is disclosed in WO2006/078593.

For details, e.g. on a process to manufacture this compound or a saltthereof, reference is thus made to these documents.

-   -   Saxagliptin (BMS-477118) having the structural formula C below        is        (1S,3S,5S)-2-{(2S)-2-amino-2-(3-hydroxyadamantan-1-yl)acetyl}-2-azabicyclo[3.1.0]hexane-3-carbonitrile,        also named        (S)-3-hydroxyadamantylglycine-L-cis-4,5-methanoprolinenitrile,

Saxagliptin is specifically disclosed in U.S. Pat. No. 6,395,767 and inExample 60 of WO 01/68603. In one embodiment, saxagliptin is in the formof its HCl salt or its mono-benzoate salt as disclosed in WO2004/052850. In a further embodiment, saxagliptin is in the form of thefree base. In a yet further embodiment, saxagliptin is in the form ofthe monohydrate of the free base as disclosed in WO 2004/052850.Crystalline forms of the HCl salt and the free base of saxagliptin aredisclosed in WO 2008/131149. A process for preparing saxagliptin is alsodisclosed in WO 2005/106011 and WO 2005/115982.

For details, e.g. on a process to manufacture this compound or a saltthereof, reference is thus made to these documents.

-   -   Denagliptin (GSK-823093) having the structural formula D below        is        (2S,4S)-1-[(2S)-2-amino-3,3-bis(4-fluorophenyl)propionyl]-4-fluoropyrrolidine-2-carbonitrile,        also named        (2S,4S)-4-fluoro-1-[4-fluoro-beta-(4-fluorophenyl)-L-phenylalanyl]-2-pyrrolidinecarbonitrile

Denagliptin is specifically disclosed in U.S. Pat. No. 7,132,443 and inWO 03/002531. In one embodiment, denagliptin is in the form of itshydrochloride salt as disclosed in Example 2 of WO 03/002531 or itstosylate salt as disclosed in WO 2005/009956. A class of this embodimentrefers to denagliptin tosylate. Crystalline anhydrous denagliptintosylate is disclosed in WO 2005/009956.

For details, e.g. on a process to manufacture this compound or a saltthereof, reference is thus made to these documents.

-   -   Alogliptin (SYR-322) having the structural formula E below is        2-({6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl}methyl)benzonitrile

Alogliptin is specifically disclosed in US 2005/261271, EP 1586571 andin WO 2005/095381. In one embodiment, alogliptin is in the form of itsbenzoate salt, its hydrochloride salt or its tosylate salt each asdisclosed in WO 2007/035629. A class of this embodiment refers toalogliptin benzoate. Polymorphs of alogliptin benzoate are disclosed inWO 2007/035372. A process for preparing alogliptin is disclosed in WO2007/112368 and, specifically, in WO 2007/035629.

For details, e.g. on a process to manufacture this compound or a saltthereof, reference is thus made to these documents.

-   -   (S)-1-((2S,3S,11bS)-2-Amino-9,10-dimethoxy-1,3,4,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one        or a pharmaceutically acceptable salt thereof:

This compound and methods for its preparation are disclosed in WO2005/000848. A process for preparing this compound (specifically itsdihydrochloride salt) is also disclosed in WO 2008/031749, WO2008/031750 and WO2008/055814.

For details, e.g. on a process to manufacture this compound or a saltthereof, reference is thus made to these documents.

-   -   (R)-2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile        or a pharmaceutically acceptable salt thereof:

This compound and methods for its preparation and use are disclosed inWO 2005/095381, US 2007060530, WO 2007/033350, WO 2007/035629, WO2007/074884, WO 2007/112368 and WO 2008/033851. Specifically claimedsalts include the succinate (WO 2008/067465), benzoate,benzenesulfonate, p-toluenesulfonate, (R)-mandelate and hydrochloride.For details, e.g. on a process to manufacture this compound or a saltthereof, reference is thus made to these documents.

Partner drugs to be combined with the DPP-4 inhibitors within thepharmaceutical compositions according to this invention are biguanides(e.g. metformin such as metformin hydrochloride), thiazolidinones (e.g.pioglitazone such as pioglitazone hydrochloride), statines (e.g.atorvastatin) or ARBs (e.g. telmisartan).

The biguanide antihyperglycemic agent metformin is disclosed in U.S.Pat. No. 3,174,901. The preparation of metformin (dimethyldiguanide) andits hydrochloride salt is state of the art and was disclosed first byEmil A. Werner and James Bell, J. Chem. Soc. 121, 1922, 1790-1794. Otherpharmaceutically acceptable salts of metformin can be found in U.S.application Ser. No. 09/262,526 filed Mar. 4, 1999 or U.S. Pat. No.3,174,901. It is preferred that the metformin employed herein be themetformin hydrochloride salt.

Unless specifically noted, in the present context the terms “DPP-4inhibitor(s)”, “biguanide(s)”, “thiazolidinone(s)”, “statine(s)”,“ARB(s)”, or any species thereof like “metformin”, “pioglitazone”, arealso intended to comprise any pharmaceutically acceptable salt thereof,crystal form, hydrate, solvate, diastereomer or enantiomer thereof.

For avoidance of any doubt, the disclosure of each of the foregoingdocuments cited above is specifically incorporated herein by referencein its entirety.

In attempts to prepare pharmaceutical compositions of selected DPP-4inhibitors it has been observed, that the DPP-4 inhibitors with aprimary or secondary amino group show incompatibilities, degradationproblems, or extraction problems with a number of customary excipientssuch as microcrystalline cellulose, sodium starch glycolate,croscarmellose sodium, tartaric acid, citric acid, glucose, fructose,saccharose, lactose, maltodextrines.

Though the compounds themselves are very stable, they react withincompatible partner drug, or its impurity product, and/or with manyexcipients used in solid dosage forms and with impurities of excipients,especially in tight contact provided in tablets and at highexcipient/drug ratios. The amino group appears to react with reducingsugars and with other reactive carbonyl groups and with carboxylic acidfunctional groups formed for example at the surface of microcrystallinecellulose by oxidation. These unforeseen difficulties are primarilyobserved in low dosage ranges of the DPP-4 inhibitor used, which arerequired due to their surprising potency, and/or high dosage ranges ofthe partner drug used. Thus, pharmaceutical compositions are required tosolve these technical problems, which may be associated with theunexpected potency of selected DPP-4 inhibitor compounds.

Other aims of the present invention will become apparent to the skilledman from the foregoing and following remarks.

It has now been found that the pharmaceutical compositions, which aredescribed in greater details herein, have surprising and particularlyadvantageous properties.

In particular, it has been found that by the use of a nucleophilicand/or basic agent, which may be suitable for stabilizing, such as e.g.a suitable buffering agent as stabilizer, within these pharmaceuticalcompositions one can overcome these problems, e.g. of incompatibilityand poor stability, especially decomposition and/or “assay decrease”which may be caused e.g. by reaction (e.g. by acylation, urea formationor Maillard reaction, or the like) of free base type DPP-4 inhibitorswhen combined with an incompatible partner drug, or its impurity productand/or a pharmaceutical excipient having such functional group (such asa reducing end of a sugar or an acyl group, such as e.g. an acetyl orcarbamoyl group) to form derivatives with the free base type DPP-4inhibitors, such as e.g. N-acetyl or N-carbamoyl derivatives. Therefore,by the use of a suitable nucleophilic and/or basic agent (e.g. abuffering and/or pH modifying agent) within these pharmaceuticalcompositions protection against decomposition and degradation can beachieved.

Thus, the present invention is directed to a chemically stable FDCformulation comprising a DPP-4 inhibitor, a partner drug, and anucleophilic and/or basic agent.

Thus, the present invention is also directed to a chemically stable FDCformulation comprising a DPP-4 inhibitor, a partner drug, and a suitablebuffering agent.

Thus, the present invention is also directed to a chemically stable FDCformulation comprising a DPP-4 inhibitor, a partner drug, and a pHmodifying agent.

A DPP-4 inhibitor within the meaning of the present invention includes,without being limited to, any of those DPP-4 inhibitors mentionedhereinabove and hereinbelow, preferably orally active DPP-4 inhibitors.

In a closer embodiment, a DPP-4 inhibitor within the meaning of thepresent invention includes a DPP-4 inhibitor with an amino group,especially a free or primary amino group.

In a yet closer embodiment, a DPP-4 inhibitor in the context of thepresent invention is a DPP-4 inhibitor with a primary amino group,particularly with a free primary amino group.

The partner drug used is selected from the group consisting of abiguanide (e.g. metformin such as metformin hydrochloride), athiazolidinone (e.g. pioglitazone such as pioglitazone hydrochloride), astatine (e.g. atorvastatin) and an ARB (e.g. telmisartan). A preferredpartner drug within the meaning of this invention is metformin,particularly metformin hydrochloride (1,1-dimethylbiguanidehydrochloride or metformin HCl).

The buffering agent used may be a basic amino acid, which has anintramolecular amino group and alkaline characteristics (isoelectricpoint, pI: 7.59-10.76), such as e.g. L-arginine, L-lysine orL-histigine. A preferred buffering agent within the meaning of thisinvention is L-arginine. L-Arginine has a particular suitablestabilizing effect on the compositions of this invention, e.g. bysuppressing degradation of the DPP-4 inhibitor in the presence of thepartner drug.

The present invention is directed to a pharmaceutical comprising a DPP-4inhibitor, a partner drug, a nucleophilic and/or basic agent, and one ormore pharmaceutical excipients.

The present invention is also directed to a pharmaceutical compositioncomprising a DPP-4 inhibitor, a partner drug, a suitable bufferingagent, and one or more pharmaceutical excipients.

The present invention is also directed to a pharmaceutical comprising aDPP-4 inhibitor, a partner drug, a pH modifying agent, and one or morepharmaceutical excipients.

In an embodiment, the present invention is directed to a pharmaceuticalcomposition (e.g. an oral solid dosage form, particularly a tablet)comprising a DPP-4 inhibitor; a partner drug (particularly metformin);and L-arginine for stabilizing the composition and/or the DPP-4inhibitor, particularly against chemical degradation; as well as one ormore pharmaceutical excipients.

In another embodiment, the present invention is directed to apharmaceutical composition (e.g. an oral solid dosage form, particularlya tablet) obtainable from a DPP-4 inhibitor; a partner drug(particularly metformin); and L-arginine for stabilizing the compositionand/or the DPP-4 inhibitor, particularly against chemical degradation;as well as one or more pharmaceutical excipients.

In general, pharmaceutical excipients which may be used may be selectedfrom the group consisting of one or more fillers, one or more binders ordiluents, one or more lubricants, one or more disintegrants, and one ormore glidants, one or more film-coating agents, one or moreplasticizers, one or more pigments, and the like.

The pharmaceutical compositions (tablets) of this invention compriseusually a binder.

In more detail, the pharmaceutical compositions (tablets) of thisinvention comprise usually one or more fillers (e.g. D-mannitol, cornstarch and/or pregelatinized starch), a binder (e.g. copovidone), alubricant (e.g. magnesium stearate), and a glidant (e.g. colloidalanhydrous silica).

Suitably the pharmaceutical excipients used within this invention areconventional materials such as D-mannitol, corn starch, pregelatinizedstarch as a filler, copovidone as a binder, magnesium stearate as alubricant, colloidal anhydrous silica as a glidant, hypromellose as afilm-coating agent, propylene glycol as a plasticizer, titanium dioxide,iron oxide red/yellow as a pigment, and talc, etc.

A typical composition according to the present invention comprises thebinder copovidone (also known as copolyvidone or Kollidon VA64).

Further, a typical composition according to the present inventioncomprises the filler corn starch, the binder copovidone, the lubricantmagnesium stearate, and the glidant colloidal anhydrous silica.

A pharmaceutical composition according to an embodiment of the presentinvention is intended for the treatment of diabetes and/or to achieveglycemic control in a type 1 or type 2 diabetes mellitus patient andcomprises a fixed dose combination formulation as described hereintogether with suitable pharmaceutical excipients. Additionally thecompositions can be used to treat rheumatoid arthritis, obesity andosteoporosis as well as to support allograft transplantation.

Thus, in particular, the present invention is directed to apharmaceutical composition (especially an oral solid dosage form,particularly a tablet) comprising a DPP-4 inhibitor, metforminhydrochloride, L-arginine and one or more pharmaceutical excipients,particularly one or more fillers, one or more binders, one or moreglidants, and/or one or more lubricants.

In more particular, the present invention is directed to apharmaceutical composition (especially an oral solid dosage form,particularly a tablet) comprising a DPP-4 inhibitor, metforminhydrochloride, L-arginine, copovidone as binder and one or more furtherpharmaceutical excipients.

Typical pharmaceutical compositions of this invention may comprise inthe DPP-4 inhibitor portion 0.1-10 L-arginine (such as e.g. about 0.1%,0.25%, 0.556%, 2.12%, 2.22% or 10%) by weight of total DPP-4 inhibitorportion, particularly about 2% (e.g. more specifically, 2.12% by weightof total tablet core of uncoated monolayer tablet).

Typical pharmaceutical compositions of this invention may comprise inthe DPP-4 inhibitor portion (% by weight of total DPP-4 inhibitorportion):

0.2-10% DPP-4 inhibitor, and 0.1-10% L-arginine.

Typical pharmaceutical compositions of this invention may comprise theDPP-4 inhibitor and L-arginine in a weight ratio of from about 1:20 toabout 10:1 or from about 1:15 to about 10:1 or from about 1:10 to about10:1, especially from 1:10 to 5:2, such as e.g. in a weight ratio of1:10, 1:8.5, 1:5, 1:1, or 1:0.4, more detailed in a weight ratio of 2.5mg:25 mg, 2.5 mg:21.2 mg, 2.5 mg:12.5 mg, 2.5 mg:2.5 mg, or 2.5 mg:1 mg.

Typical pharmaceutical compositions of this invention may comprisemetformin hydrochloride and L-arginine in a weight ratio of from about40:1 to about 1000:1, such as e.g. in a weight ratio of 40:1, 200:1,340:1, 400:1, 500:1, 850:1, or 1000:1, more detailed in a weight ratioof 500 mg:12.5 mg, 850 mg:21.2 mg, 1000 mg:25 mg, 500 mg:2.5 mg, 850mg:2.5 mg, 1000 mg:2.5 mg, 500 mg:1 mg, 850 mg:1 mg, or 1000 mg:1 mg.

Typical pharmaceutical compositions of this invention may comprise theDPP4-inhibitor, metformin hydrochloride and L-arginine in a weight ratioof from about 1:200:0.4 to about 1:200:5 (e.g. 1:200:0.4, 1:200:1,1:200:5), or from about 1:340:0.4 to about 1:340:8.5 (e.g. 1:340:0.4,1:340:1, 1:340:8.5), or from about 1:400:0.4 to about 1:400:10 (e.g.1:400:0.4, 1:400:1, 1:400:10).

Typical pharmaceutical compositions of this invention may comprise oneor more of the following amounts (% by weight of total coated tabletmass):

0.1-0.5% DPP-4 inhibitor,  47-85% metformin HCl, 0.07-2.2%  L-arginine,3.9-8.1% binder (e.g. copovidone), 2.3-5.9% filler 1 (e.g. corn starch), 0-4.4% filler 2 (e.g. pregelatinized starch),  0-33% filler 3 (e.g.D-mannitol), 0.7-1.5% lubricant (e.g. magnesium stearate), and 0.1-0.5%glidant (e.g. colloidal anhydrous silica).

Further details about the FDC formulations of this invention, e.g. theingredients, ratio of ingredients (such as e.g. ratio of DPP-4inhibitor, metformin hydrochloride, L-arginine and/or excipients),particularly with respect to special dosage forms (tablets) used withinthis invention as well as their preparation, become apparent to theskilled person from the disclosure hereinbefore and hereinafter(including by way of example the following examples as well as theclaims).

In a first embodiment (embodiment A), a DPP-4 inhibitor in the contextof the present invention is any DPP-4 inhibitor of formula (I)

or formula (II)

or formula (III)

wherein R1 denotes ([1,5]naphthyridin-2-yl)methyl,(quinazolin-2-yl)methyl, (quinoxalin-6-yl)methyl,(4-methyl-quinazolin-2-yl)methyl, 2-cyano-benzyl,(3-cyano-quinolin-2-yl)methyl, (3-cyano-pyridin-2-yl)methyl,(4-methyl-pyrimidin-2-yl)methyl, or (4,6-dimethyl-pyrimidin-2-yl)methyland R2 denotes 3-(R)-amino-piperidin-1-yl,(2-amino-2-methyl-propyl)-methylamino or(2-(S)-amino-propyl)-methylamino,or its pharmaceutically acceptable salt;

In a second embodiment (embodiment B), a DPP-4 inhibitor in the contextof the present invention is a DPP-4 inhibitor selected from the groupconsisting of sitagliptin, vildagliptin, saxagliptin and alogliptin, orits pharmaceutically acceptable salt.

Regarding the first embodiment (embodiment A), preferred DPP-4inhibitors are any or all of the following compounds and theirpharmaceutically acceptable salts:

-   -   1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine        (compare WO 2004/018468, example 2 (142):

-   -   1-[([1,5]naphthyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine        (compare WO 2004/018468, example 2 (252)):

-   -   1-[(Quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine        (compare WO 2004/018468, example 2 (80)):

-   -   2-((R)-3-Amino-piperidin-1-yl)-3-(but-2-yinyl)-5-(4-methyl-quinazolin-2-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one        (compare WO 2004/050658, example 136):

-   -   1-[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyin-1-yl)-8-[(2-amino-2-methyl-propyl)-methylamino]-xanthine        (compare WO 2006/029769, example 2 (1)):

-   -   1-[(3-Cyano-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine        (compare WO 2005/085246, example 1 (30)):

-   -   1-(2-Cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine        (compare WO 2005/085246, example 1 (39)):

-   -   1-[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-(2-amino-propyl)-methylamino]-xanthine        (compare WO 2006/029769, example 2 (4)):

-   -   1-[(3-Cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine        (compare WO 2005/085246, example 1 (52)):

-   -   1-[(4-Methyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine        (compare WO 2005/085246, example 1 (81)):

-   -   1-[(4,6-Dimethyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine        (compare WO 2005/085246, example 1 (82)):

-   -   1-[(Quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine        (compare WO 2005/085246, example 1 (83)):

These DPP-4 inhibitors are distinguished from structurally comparableDPP-4 inhibitors, as they combine exceptional potency and a long-lastingeffect with favourable pharmacological properties, receptor selectivityand a favourable side-effect profile or bring about unexpectedtherapeutic advantages or improvements when combined with otherpharmaceutical active substances. Their preparation is disclosed in thepublications mentioned.

A more preferred DPP-4 inhibitor among the abovementioned DPP-4inhibitors of embodiment A of this invention is1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine,particularly the free base thereof (which is also known as BI 1356).

Regarding the second embodiment (embodiment B), preferred DPP-4inhibitors are selected from the group consisting of vildagliptin,saxagliptin and alogliptin, and their pharmaceutically acceptable salts.

Unless otherwise noted, according to this invention it is to beunderstood that the definitions of the above listed DPP-4 inhibitorsalso comprise their pharmaceutically acceptable salts as well ashydrates, solvates and polymorphic forms thereof. With respect to salts,hydrates and polymorphic forms thereof, particular reference is made tothose which are referred to hereinabove and hereinbelow.

With respect to embodiment A, the methods of synthesis for the DPP-4inhibitors according to embodiment A of this invention are known to theskilled person. Advantageously, the DPP-4 inhibitors according toembodiment A of this invention can be prepared using synthetic methodsas described in the literature. Thus, for example, purine derivatives offormula (I) can be obtained as described in WO 2002/068420, WO2004/018468, WO 2005/085246, WO 2006/029769 or WO 2006/048427, thedisclosures of which are incorporated herein. Purine derivatives offormula (II) can be obtained as described, for example, in WO2004/050658 or WO 2005/110999, the disclosures of which are incorporatedherein. Purine derivatives of formula (III) can be obtained asdescribed, for example, in WO 2006/068163, WO 2007/071738 or WO2008/017670, the disclosures of which are incorporated herein. Thepreparation of those DPP-4 inhibitors, which are specifically mentionedhereinabove, is disclosed in the publications mentioned in connectiontherewith. Polymorphous crystal modifications and formulations ofparticular DPP-4 inhibitors are disclosed in WO 2007/128721 and WO2007/128724, respectively, the disclosures of which are incorporatedherein in their entireties.

With respect to embodiment B, the methods of synthesis for the DPP-4inhibitors of embodiment B are described in the scientific literatureand/or in published patent documents, particularly in those citedherein.

With respect to the first embodiment (embodiment A), the dosagetypically required of the DPP-4 inhibitors mentioned herein inembodiment A when administered orally is 0.5 mg to 100 mg, preferably2.5 mg to 50 mg or 0.5 mg to 10 mg, more preferably 2.5 mg to 10 mg or 1mg to 5 mg, in each case 1 to 4 times a day. Thus, the dosage requiredof1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinewhen administered orally is 0.5 mg to 10 mg per patient per day,preferably 2.5 mg to 10 mg or 1 mg to 5 mg per patient per day.

A dosage form prepared with a pharmaceutical composition comprising aDPP-4 inhibitor mentioned herein in embodiment A contain the activeingredient in a dosage range of 0.1-100 mg, in particular 0.5 to 10 mg.Thus, particular dosage strengths of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthineare 0.5 mg, 1 mg, 2.5 mg, 5 mg and 10 mg. A more particular unit dosagestrength of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefor inclusion into fixed dose combination pharmaceutical compositions ofthe present invention is 2.5 mg.

With respect to the second embodiment (embodiment B), the doses of DPP-4inhibitors mentioned herein in embodiment B to be administered tomammals, for example human beings, of, for example, approximately 70 kgbody weight, may be generally from about 0.5 mg to about 350 mg, forexample from about 10 mg to about 250 mg, preferably 20-200 mg, morepreferably 20-100 mg, of the active moiety per person per day, or fromabout 0.5 mg to about 20 mg, preferably 2.5-10 mg, per person per day,divided preferably into 1 to 4 single doses which may, for example, beof the same size. Single dosage strengths comprise, for example, 2.5, 5,10, 25, 40, 50, 75, 100, 150 and 200 mg of the DPP-4 inhibitor activemoiety.

A dosage strength of the DPP-4 inhibitor sitagliptin is usually between25 and 200 mg of the active moiety. A recommended dose of sitagliptin is100 mg calculated for the active moiety (free base anhydrate) oncedaily. Unit dosage strengths of sitagliptin free base anhydrate (activemoiety) are 25, 50, 75, 100, 150 and 200 mg. Particular unit dosagestrengths of sitagliptin (e.g. per tablet) are 25, 50 and 100 mg. Anequivalent amount of sitagliptin phosphate monohydrate to thesitagliptin free base anhydrate is used in the pharmaceuticalcompositions, namely, 32.13, 64.25, 96.38, 128.5, 192.75, and 257 mg,respectively. Adjusted dosages of 25 and 50 mg sitagliptin are used forpatients with renal failure.

A dosage range of the DPP-4 inhibitor vildagliptin is usually between 10and 150 mg daily, in particular between 25 and 150 mg, 25 and 100 mg or25 and 50 mg or 50 and 100 mg daily. Particular examples of daily oraldosage are 25, 30, 35, 45, 50, 55, 60, 80, 100 or 150 mg. In a moreparticular aspect, the daily administration of vildagliptin is between25 and 150 mg or between 50 and 100 mg. In another more particularaspect, the daily administration of vildagliptin is 50 or 100 mg. Theapplication of the active ingredient may occur up to three times a day,preferably one or two times a day. Particular dosage strengths are 50 mgor 100 mg vildagliptin.

Metformin is usually given in doses varying from about 250 mg to 3000mg, particularly from 500 mg to 2000 mg up to 2500 mg per day usingvarious dosage regimens.

A dosage range of the partner drug metformin is usually from 100 mg to500 mg or 200 mg to 850 mg (1-3 times a day), or from 300 mg to 1000 mgonce or twice a day.

The unit dosage strengths of the metformin hydrochloride for use in thepresent invention may be from 100 mg to 2000 mg or from 250 mg to 2000mg, preferably from 250 mg to 1000 mg. Particular dosage strengths maybe 250, 500, 625, 750, 850 and 1000 mg of metformin hydrochloride. Theseunit dosage strengths of metformin hydrochloride represent the dosagestrengths approved in the US for marketing to treat type 2 diabetes.More particular unit dosage strengths of metformin hydrochloride forincorporation into the fixed dose combination pharmaceuticalcompositions of the present invention are 500, 850 and 1000 mg ofmetformin hydrochloride.

A dosage of the partner drug pioglitazone is usually 1-10 mg, 15 mg, 30mg, or 45 mg once a day.

A dosage of the partner drug telmisartan is usually from 20 mg to 320 mgor 40 mg to 160 mg per day.

A dosage of the partner drug atorvastatin is usually from 1 mg to 40 mgor 10 mg to 80 mg once a day

The amount of the DPP-4 inhibitor and of the partner drug in thepharmaceutical composition according to this invention correspond to therespective dosage ranges as provided hereinbefore. For example, apharmaceutical composition comprises1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinein an amount of 0.5 mg to 10 mg (namely 0.5 mg, 1 mg, 2.5 mg, 5 mg or 10mg) and of metformin hydrochloride in an amount of 250 mg to 1000 mg(namely 250, 500, 625, 750, 850 or 1000 mg).

Specific embodiments of dosage strengths for1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthineand metformin hydrochloride in the fixed dose combinations of thepresent invention are the following:

(1) 2.5 mg of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base, and 500 mg metformin hydrochloride;

(2) 2.5 mg of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base, and 850 mg metformin hydrochloride;

(3) 2.5 mg of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base, and 1000 mg metformin hydrochloride.

The particular fixed dose combinations of BI 1356 and metformin of thepresent invention may be administered once or twice daily to thepatient, in particular twice daily.

In a preferred aspect of the present invention, the present invention isdirected to a pharmaceutical composition (especially an oral soliddosage form, particularly a tablet) comprising or obtainable from

a DPP-4 inhibitor selected from the group consisting of

1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base, vildagliptin, saxagliptin and alogliptin,

metformin hydrochloride,

L-arginine,

and one or more pharmaceutical excipients, such as e.g. those describedherein.

A particularly preferred DPP-4 inhibitor to be emphasized within themeaning of this invention is1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base (also known as BI 1356).

In particular, it has been found that L-arginine is effective asstabilizing agent for FDC combinations of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base with metformin HCl. Even after 6 months storage at acceleratedconditions L-arginine is able to suppress degradation of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base effectively. The effect seems to be concentration dependent.Thus, L-arginine may act as stabilizing and buffering agent in theformulation.

In a more preferred aspect of the present invention, the presentinvention is directed to a pharmaceutical composition (especially anoral solid dosage form, particularly a tablet) comprising or made from

1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base (BI 1356),

metformin hydrochloride,

L-arginine,

and one or more pharmaceutical excipients, such as e.g. those describedherein.

Typical pharmaceutical compositions according to this invention compriseor are made by comprising combining any one of the following amounts(1), (2) or (3) of active ingredients and L-arginine:

(1) 2.5 mg of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base, 500 mg metformin hydrochloride, and from 1.0 mg to 12.5 mgL-arginine (specifically 1.0 mg, 2.5 mg or 12.5 mg L-arginine);

(2) 2.5 mg of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base, 850 mg metformin hydrochloride, and from 1.0 mg to 21.2 mgL-arginine (specifically 1.0 mg, 2.5 mg or 21.2 mg L-arginine);

(3) 2.5 mg of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base, 1000 mg metformin hydrochloride, and from 1.0 mg to 25.0 mgL-arginine (specifically 1.0 mg, 2.5 mg or 25 mg L-arginine).

In a further aspect of the present invention, the present inventionprovides methods of manufacturing of the compositions, formulations,blends or dosage forms of this invention, such as e.g. by using methodsknown to one skilled in the art and/or in a manner as described herein,for example they may be obtained by processes comprising using (e.g.mixing, combining, blending and/or composing) the components and/oringredients, or pre-mixtures thereof, mentioned hereinbefore andhereinafter, as well as the present invention further providescompositions, formulations, blends or dosage forms obtainable by thesemethods or processes and/or obtainable from the components, ingredients,pre-mixtures and/or mixtures mentioned hereinbefore and hereinafter.

In a further aspect of the present invention, the present inventionprovides a pharmaceutical composition, formulation, blend or dosage formof this invention which is substantially free of or only marginallycomprises impurities and/or degradation products; that means, forexample, that the composition, formulation, blend or dosage fromincludes about <5%, or about <4%, or about <3%, or less than about 2%,preferably less than about 1%, more preferably less than about 0.5%,even more preferably less than about 0.2% of any individual or totalimpurity or degradation product(s) by total weight, such as e.g.N-acetyl and/or N-carbamoyl derivative of the free base type DPP-4inhibitor. The content and/or degradation can be determined bywell-known analytical methods, for example using HPLC methods.

In this context, in a further aspect of the present invention, thepresent invention provides derivatives of a DPP-4 inhibitor having anamino group, particularly a free primary amino group, as mentionedherein, said derivatives being obtainable by acetylation of the aminogroup (e.g. to yield the group —NHC(O)CH₃) or by carbamoylation of theamino group (e.g. to yield the group —NHC(O)NH₂).

Dosage Forms for the FDC Formulations of this Invention:

Another purpose of this invention is to develop the FDC formulations ofthis invention with a reasonable tablet size, with good tabletproperties (e.g. stability, hardness, friability, disintegration,content uniformity and the like) and, in a preferred embodiment, withoutdisturbing the original dissolution profiles of each mono tablet in caseof desired proof of bioequivalence with minimized risk of failure.

Designing of the dosage form is an important matter not only to optimizethe tablet size and dissolution profiles but also to minimize the amountof stabilizing agent, because the pH change by dissolving of bufferingagent may affect the dissolution profiles of the DPP-4 inhibitor or apartner drug. The selection of the dosage form is depending on the dosestrengths of the active ingredients used and their physicochemical andsolid state characteristics.

A conventional approach (i.e. physical separation) may not be useful forstabilization of certain DPP-4 inhibitors of this invention. A bufferingagent like L-arginine need to be added into the formulation forsuppressing degradation, however it may be necessary to minimize theamount of L-arginine because its alkaline characteristics give anegative impact on the dissolution profiles or the stability of theDPP-4 inhibitor or a partner drug.

Thus, it has been found that suitable dosage forms for the FDCformulations of this invention are film-coated tablets (film-coating fordrug loading, such as particularly DPP-4 inhibitor drug loading by filmcoating on tablet cores containing the partner drug), mono-layertablets, bi-layer tablets, tri-layer tablets and press-coated tablets(e.g. tablet-in-tablet or bull's eye tablet with DPP-4 inhibitor core),which dosage forms are good measures to achieve the goal underconsideration of desired pharmaceutical profiles and characteristics ofa DPP-4 inhibitor and a partner drug used.

Said dosage forms have been found to be applicable to the FDCformulations either keeping the original dissolution profiles of eachmono tablet or adjusting the profiles to desired levels, e.g. includingextended release characteristics, and a reasonable tablet size.

A typical mono-layer tablet of this invention comprises a DPP-4inhibitor, metformin hydrochloride, L-arginine, one or more fillers(such as e.g. corn starch), one or more binders (such as e.g.copovidone), one or more glidants (such as e.g. colloidal anhydroussilica) and one or more lubricants (such as e.g. magnesium stearate).

In a preferred embodiment of the present invention, the presentinvention is directed to an oral solid pharmaceutical composition,preferably a tablet, particularly a mono-layer tablet comprising or madefrom

1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine(also known as BI 1356, e.g. in an amount of 2.5 mg), metformin(particularly metformin hydrochloride, e.g. in an amount of 500 mg, 850mg or 1000 mg),

L-arginine,

and one or more pharmaceutical excipients, particularly one or morefillers (e.g. corn starch), one or more binders (e.g. copovidone), oneor more glidants (e.g. colloidal anhydrous silica) and/or one or morelubricants (e.g. magnesium stearate),

as well as, optionally, a film coat e.g. comprising one or morefilm-coating agents (e.g. hypromellose), one or more plasticizers (e.g.propylene glycol), one or more pigments (e.g. titanium dioxide, ironoxide red and/or iron oxide yellow) and/or one or more glidants (e.g.talc).

A method of manufacturing a tablet of this invention comprisestabletting (e.g. compression) of one or more final blends in form ofgranules. Granules of the (final) blend(s) according to this inventionmay be prepared by methods well-known to one skilled in the art (e.g.high shear wet granulation or fluid bed granulation). Granules accordingto this invention as well as details of granulation processes (includingtheir separate steps) for the preparation of granules of this inventionare described by way of example in the following examples.

An illustrative granulation process for the preparation of granulescomprising the mono-layer composition comprises

i.) combining (e.g. dissolving or dispersing) L-arginine, a binder (e.g.copovidone) and, optionally, the DPP-4 inhibitor (e.g. BI 1356) in asolvent or mixture of solvents such as purified water at ambienttemperature to produce a granulation liquid;

ii.) blending metformin HCl, a filler (e.g. corn starch) and,optionally, the DPP-4 inhibitor (e.g. BI 1356) in a suitable mixer (e.g.fluid-bed granulator) to produce a pre-mix;

wherein the DPP-4 inhibitor (e.g. BI 1356) may be included either in thegranulation liquid obtained in i.) or in the pre-mix obtained in ii.),preferably BI 1356 is dispersed in the granulation liquid and is absentin the pre-mix;

iii.) spraying the granulation-liquid into the pre-mix and granulatingthe mixture for example in a fluid-bed granulator, preferably under drycondition;

iv.) drying the granulate, e.g. at about 70° C. inlet air temperatureuntil the desired loss on drying value in the range of 1-2% is obtained;

v.) delumping the dried granulate for example by sieving through a sievewith a mesh size of 0.5 to 1.0 mm;

vi.) blending the sieved granulate and preferably sieved glidant (e.g.colloidal anhydrous silica) in a suitable blender;

vii.) adding preferably sieved lubricant (e.g. magnesium stearate) tothe granulate for final blending for example in the free-fall blender.

Preferentially, a mono-layer tablet according to this inventioncomprises or is obtainable from a mixture comprising any one of thefollowing amounts (1), (2) or (3) of active ingredients and L-arginine:

(1) 2.5 mg of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base, 500 mg metformin hydrochloride, and 12.5 mg L-arginine;

(2) 2.5 mg of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base, 850 mg metformin hydrochloride, and 21.2 mg L-arginine;

(3) 2.5 mg of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base, 1000 mg metformin hydrochloride, and 25 mg L-arginine.

A typical bi-layer tablet of this invention comprises

a DPP-4 inhibitor portion comprising a DPP-4 inhibitor, L-arginine, oneor more fillers (such as e.g. D-mannitol, pregelatinized starch and cornstarch), one or more binders (such as e.g. copovidone) and one or morelubricants (such as e.g. magnesium stearate), and

a metformin HCl portion comprising metformin hydrochloride, one or morefillers (such as e.g. corn starch), one or more binders (such as e.g.copovidone), one or more glidants (such as e.g. colloidal anhydroussilica) and one or more lubricants (such as e.g. magnesium stearate).

Preferentially, a bi-layer tablet according to this invention comprisesor is obtainable from a mixture comprising any one of the followingamounts (1), (2) or (3) of active ingredients and L-arginine:

(1) 2.5 mg of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base, 500 mg metformin hydrochloride, and 2.5 mg L-arginine;

(2) 2.5 mg of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base, 850 mg metformin hydrochloride, and 2.5 mg L-arginine;

(3) 2.5 mg of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base, 1000 mg metformin hydrochloride, and 2.5 mg L-arginine.

A typical press-coated tablet (tablet-in-tablet or bull's eye tablet) ofthis invention comprises a DPP-4 inhibitor core portion comprising aDPP-4 inhibitor, L-arginine, one or more fillers (such as e.g.D-mannitol, pregelatinized starch and corn starch), one or more binders(such as e.g. copovidone) and one or more lubricants (such as e.g.magnesium stearate), and

a metformin HCl portion comprising metformin hydrochloride, one or morefillers (such as e.g. corn starch), one or more binders (such as e.g.copovidone), one or more glidants (such as e.g. colloidal anhydroussilica) and one or more lubricants (such as e.g. magnesium stearate).

Preferentially, a press-coated tablet (tablet-in-tablet or bull's eyetablet) according to this invention comprises or is obtainable from amixture comprising any one of the following amounts (1), (2) or (3) ofactive ingredients and L-arginine:

(1) 2.5 mg of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base, 500 mg metformin hydrochloride, and 1.0 mg L-arginine;

(2) 2.5 mg of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base, 850 mg metformin hydrochloride, and 1.0 mg L-arginine;

(3) 2.5 mg of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base, 1000 mg metformin hydrochloride, and 1.0 mg L-arginine.

A typical film-coated tablet (DPP-4 inhibitor coating on metformin HCltablet, i.e. drug layering by film-coating for drug loading) of thisinvention comprises

a metformin HCl core portion comprising metformin hydrochloride, one ormore fillers (such as e.g. corn starch), one or more binders (such ase.g. copovidone), one or more glidants (such as e.g. colloidal anhydroussilica) and one or more lubricants (such as e.g. magnesium stearate),

wherein said core portion is seal-coated with a film coat comprising oneor more film-coating agents (such as e.g. hypromellose), one or moreplasticizers (such as e.g. propylene glycol), one or more pigments (suchas e.g. titanium dioxide, iron oxide red and/or iron oxide yellow) andone or more glidants (such as e.g. talc); and

a DPP-4 inhibitor layer comprising a DPP-4 inhibitor, L-arginine, one ormore film-coating agents (such as e.g. hypromellose) and one or moreplasticizers (such as e.g. propylene glycol).

Preferentially, a film-coated tablet (DPP4-inhibitor drug loading)according to this invention comprises or is obtainable from a mixturecomprising any one of the following amounts (1), (2) or (3) of activeingredients and L-arginine:

(1) 2.5 mg of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base, 500 mg metformin hydrochloride, and 2.5 mg L-arginine;

(2) 2.5 mg of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base, 850 mg metformin hydrochloride, and 2.5 mg L-arginine;

(3) 2.5 mg of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base, 1000 mg metformin hydrochloride, and 2.5 mg L-arginine.

Preferably, these abovementioned tablets (mono-, bi-layer, press-coatedand drug-coated tablets) are further over-coated with a final film coat,which comprises a film-coating agent (such as e.g. hypromellose), aplasticizer (such as e.g. propylene glycol), pigments (such as e.g.titanium dioxide, iron oxide red and/or iron oxide yellow) and a glidant(such as e.g. talc). Typically this additional film over-coat mayrepresent 1-4%, preferentially 1-2%, of the total mass of thecomposition.

The following dosage forms of the invention can be applied to the FDCformulation of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base (BI 1356) and metformin hydrochloride based on thecharacteristics of drug substances and requirements of the desiredpharmaceutical profiles:

a) Mono-Layer Tablets

Mono-layer tablets with L-arginine show satisfactory stability results,good dissolution properties and good content uniformity (CU). Mono-layertablets can be manufactured using conventional technologies (includingfluid-bed granulation for the DPP-4 inhibitor and metforminhydrochloride, e.g. comprising adding the DPP-4 inhibitor as powder oras an aqueous suspension in the granulation liquid to the fluid bedgranulator).

b) Bi-Layer Tablets

Bi-layer tablets with L-arginine show promising stability results, gooddissolution properties and good CU. Bi-layer tablets can be manufacturedusing conventional bi-layer tableting technologies (e.g. rotary bi-layertableting machine).

c) Press-Coated Tablets

Press-coated tablets (tablet-in-tablets and advanced press-coated bull'seye tablets) show promising stability, good CU and dissolution.Press-coated tablets can be manufactured using conventionalpress-coating technology, such as e.g. on a Kilian tablet press toobtain tablet-in-tablet or on other conventional press-coater to obtainbull's eye tablet. As an advantage of this approach, it is easy tominimize the amount of L-arginine in the formulation and control theassay and CU of the DPP-4 inhibitor portion (very small amount of drugloading; 2.5 mg/tablet where the dose strengths of metformin HCl are500, 850 and 1000 mg/tablet). Another advantage is that DPP-4 inhibitor-and metformin HCl-portion can be designed flexibly to minimize thetablet size. A modified press-coated tablet named “bull's eye tablet”may be a universal dosage potentially for bi-layer tablets as well asother FDC. Bull's eye tablet can be manufactured in a one-steppress-coating without separate core formation (like in bi-layertableting) being necessary.

It is to be noted that within the meaning of this invention the skilledperson is aware about what is meant with the phrase “bull's eye tablet”used herein. As it known to the skilled person, this tablet (alsoreferred to as an inlay tablet or a dot) is composed of an outer coatand an inner core, and in which, instead of the inner core zone beingcompletely surrounded by the outer coat, one surface of the zonecorresponding to the inner core zone is exposed.

d) Film-Coated Tablets (Drug Layering by Film-Coating for Drug Loading)

Coating of DPP-4 inhibitor drug substance on the metformin HCl tabletsshows acceptable dissolution results and promising stability data.L-arginine needs to be added into film-coating for stabilization. As anadvantage for this approach, it is possible to integrate DPP-4 inhibitorportion into a partner drug portion as it is, even if the dosage form isa modified/controlled release formulation. Within the film-coatingprocess coating endpoint determination is necessary via analytics.

The method of layering of the DPP-4 inhibitor by film-coating asdescribed herein (including the steps of seal-coating, drug-loading and,optional, over-coating) may be applied to any kind of cores or tabletswhich may comprise an active ingredient (e.g. a partner drug asmentioned herein), for example metformin cores or tablets, such as e.g.immediate release metformin tablets, sustained release metformintablets, extended release metformin tablets, modified release metformintablets, controlled release metformin tablets or delayed releasemetformin tablets. Thus, the present invention further relates to atablet which comprises a film-coat layer comprising the DPP-4 inhibitor,a film-forming agent (e.g. hypromellose), a plasticizer (e.g. propyleneglycol) and L-arginine, or which is obtainable by comprising using sucha method of layering of the DPP-4 inhibitor by film-coating as describedherein. The present invention also relates to a FDC tablet comprising animmediate or extended release metformin tablet core, a seal coat, afilm-coat layer comprising the DPP-4 inhibitor, and, optionally, anover-coat; e.g. each as described herein, as well as to such a FDCtablet made by a process comprising the following steps of seal-coatingon a metformin tablet core, layering of a DPP-4 inhibitor byfilm-coating and, optional, over-coating, e.g. each step such asdescribed herein.

Pharmaceutical immediate release dosage forms of this inventionpreferably have dissolution properties such that after 45 minutes foreach of the active ingredients at least 75%, even more preferably atleast 90% by weight of the respective active ingredient is dissolved. Ina particular embodiment, after 30 minutes for each of the activeingredients especially of the mono-layer tablet according to thisinvention (including tablet core and film-coated tablet) at least 70-75%(preferably at least 80%) by weight of the respective active ingredientis dissolved. In a further embodiment, after 15 minutes for each of theactive ingredients especially of the mono-layer tablet according to thisinvention (including tablet core and film-coated tablet) at least 55-60%by weight of the respective active ingredient is dissolved. Thedissolution properties can be determined in standard dissolution tests,e.g. according to standard pharmacopeias (e.g. using paddle method withagitation speed of 50 rpm, 0.1 M hydrochloric acid as dissolution mediumat a temperature of 37° C., and HPLC (BI 1356) and UV (metformin)analysis of the samples).

In the pharmaceutical compositions and pharmaceutical dosage formsaccording to the invention BI 1356, for example a crystalline formthereof, preferably has a particle size distribution (preferably byvolume) such that at least 90% of the respective active pharmaceuticalingredient has a particle size smaller than 200 μm, i.e. X90<200 μm,more preferably X90≦150 μm. More preferably the particle sizedistribution is such that X90≦100 μm, even more preferably X90≦75 μm. Inaddition the particle size distribution is preferably such that X90≧0.1μm, more preferably X90≧1 μm, most preferably X90≧5 μm. Thereforepreferred particle size distributions are such that 0.1 μm<X90<200 μm,particularly 0.1 μm<X90≦150 μm, more preferably 1 μm≦X90≦150 μm, evenmore preferably 5 μm≦X90≦100 μm. A preferred example of a particle sizedistribution of BI 1356 is such that X90≦50 μm or 10 μm≦X90≦50 μm. Itcan be found that a pharmaceutical composition comprising BI 1356 with aparticle size distribution as indicated hereinbefore shows desiredproperties (e.g. with regard to dissolution, content uniformity,production, or the like). The indicated particle size properties aredetermined by laser-diffraction method, in particular low angle laserlight scattering, i.e. Fraunhofer diffraction. Alternatively, theparticle size properties can be also determined by microscopy (e.g.electron microscopy or scanning electron microscopy). The results of theparticle size distribution determined by different techniques can becorrelated with one another.

Optimized Formulation of Metformin HCl Portion:

Another purpose of this invention is to provide improved formulations ofthe metformin HCl portion of the pharmaceutical compositions accordingto this invention.

For the metformin HCl part a high drug load is advantageous to beachieved as a pre-requisite for a reasonable small tablet size.

Thus, it has been found that drug load of metformin HCl andcompactability (compression force-crushing strength profile) of thetablets of this invention can be improved by surface treatment ofmetformin HCl with a water-soluble polymer, particularly copolyvidone.

Several water-soluble polymers including polyvinyl alcohol (PVA),hypromellose (HPMC), hydroxypropyl cellulose (HPC), methyl cellulose(MC), Povidone (PVP) and copolyvidone may be tested to improvecompactability (compression force-crushing strength profile). As theresults, PVA shows the best effect in terms of compactability but themanufacturability can be poor due to sticking problem during fluid-bedgranulation. Further on, PVA may be not finally selected because of itsnegative impact on the stability of certain DPP-4 inhibitors of thisinvention.

Formulation optimization studies have identified a composition with over84% drug load of metformin HCl and improved crushing strength bysurface-treatment of metformin HCl with the water-soluble polymercopolyvidone.

Therefore, finally, copolyvidone is selected and the amount can beoptimized, advantageously resulting in stable formulations and theviscosity of the granulating solution is enough low to prepare theaqueous solution and operate spraying by a fluid-bed granulator.

In optional addition, it has been found that heating/drying of metforminHCl drug substance is effective to improve the stability of certainDPP-4 inhibitors of this invention in combination with metformin HCl.The pre-treatment for metformin HCl needs to be conducted beforestarting of granulation with the DPP-4 inhibitor. The heating/drying at80° C. with a fluid-bed granulator may be helpful to reduce an excessiveamount of volatile impurities (which might be urea) in the metforminHCl.

The present invention is not to be limited in scope by the specificembodiments described herein. Various modifications of the invention inaddition to those described herein may become apparent to those skilledin the art from the present disclosure. Such modifications are intendedto fall within the scope of the appended claims.

All patent applications cited herein are hereby incorporated byreference in their entireties.

Further embodiments, features and advantages of the present inventionmay become apparent from the following examples. The following examplesserve to illustrate, by way of example, the principles of the inventionwithout restricting it.

EXAMPLES 1. Mono-Layer Tablet

The composition of mono-layer tablets for a DPP-4 inhibitor of thisinvention (BI 1356)+metformin HCl FDC (Film-coated Tablets) is shown inTable 1.

TABLE 1 Composition of BI 1356 + Metformin HCl FDC Mono-layer TabletsDose Strength (BI 1356/metformin HCl), mg 2.5/500 2.5/850 2.5/1000Ingredient [mg] [%] [mg] [%] [mg] [%] BI 1356 2.50 0.42 2.50 0.25  2.500.21 Metformin Hydrochloride 500.0   84.75 850.00  85.00 1000.00  84.75L-Arginine 12.50  2.12 21.20  2.12 25.00 2.12 Corn starch 20.00  3.3933.10  3.31 42.50 3.60 Copovidone 47.50  8.05 80.50  8.05 95.00 8.05Colloidal Anhydrous Silica 2.50 0.42 4.20 0.42  5.00 0.42 Magnesiumstearate 5.00 0.85 8.50 0.85 10.00 0.85 Purified water* 186**   315**  372**   Total Mass (tablet core) 590.00  100.00 1000.00   100.001180.00  100.00 Hypromellose (5 mPa * s) 6.00 50.00 8.00 50.00  9.0050.00 Propylene glycol 0.60 5.00 0.80 5.00  0.90 5.00 Talc 2.88 18.502.96 18.50  4.455 18.50 Titanium dioxide 2.40 25.00 4.00 25.00  3.6025.00 Iron oxide, yellow 0.12 1.25 0.20 1.25 Iron oxide, red 0.04 0.25 0.045 1.25 Purified water** 88**   117**   132**   Total Mass(film-coat) 12.00  100.00 16.00  100.00 18.00 100.00 Total Mass (coatedtablet) 602.00  1016.00   1198.00  **Removed during processing, does notappear in final product

Manufacturing Procedure (Mono-Layer Tablets):

DPP-4 inhibitor of this invention (e.g. BI 1356)+metformin HCl FDCmono-layer tablets are produced by a fluid-bed granulation process and aconventional tableting process with a rotary press. Optionally,metformin HCl and corn starch may be pre-treated by heating in a chamberof fluid-bed granulator to remove excessive HCl and/or impurity productsbefore mixing with the active DPP-4 inhibitor ingredient. After theoptional pre-treatment of metformin HCl and corn starch, the DPP-4inhibitor is either added as powder and premixed before fluid-bedgranulation is conducted by spraying of “Granulation Liquid” composed ofcopolyvidon (Kollidon VA64), L-arginine and purified water, or directlydispersed in the “granulation liquid”. After finishing of fluid-bedgranulation, the granulate is sieved with a suitable screen. The sievedgranulate is blended with colloidal anhydrous silica (Aerosil 200) andmagnesium stearate as a lubricant. The final mixture is compressed intotablets using a conventional rotary tablet press.

The tablet cores may be film-coated by an aqueous film-coatingsuspension, containing hypromellose as film-forming agent, propyleneglycol as plasticizer, talc as glidant and the pigments yellow ironoxide and/or red iron oxide and titanium dioxide.

Narrative More Specific Description of the Preferred ManufacturingProcess for the Mono-Layer Tablets:

a) Metformin HCl and corn starch are sieved using a screen with a meshsize of 0.5 to 1 mm before dispensing.b) L-arginine, BI 1356 and finally copolyvidon are dissolved resp.dispersed in purified water at ambient temperature with a propellermixer to produce the “Granulation Liquid”.c) Metformin HCl and corn starch are sucked into a chamber of a suitablefluid-bed granulator and preheated up to a product temperature target ofapprox. 36° C.d) Immediately after the product temperature target is reached, the“Granulation Liquid” is sprayed into the mixture for fluid-bedgranulating under dry condition to avoid blocking during granulation.e) At the end of spraying, the resultant granulate is dried at approx.70 C inlet air temperature until the desired LOD value (i.e. 1-2%) isreached.f) The granulate is sieved using a screen with a mesh size of 0.5 to 1.0mm.g) The sieved granulate and colloidal anhydrous silica (Aerosil 200) areblended with a suitable blender. Aerosil 200 should be pre-sieved with asmall portion of the sieved granulate through a 0.8 mm-screen beforeuse.h) Magnesium stearate is passed through a 0.8 mm sieve and added intothe granulate. Subsequently the “Final Blend” is produced by finalblending in the free-fall blender.i) The “Final Blend” is compressed into tablets with a rotary press.j) Titanium dioxide, propylene glycol and iron oxide (yellow, red oryellow and red) are dispersed in purified water with a high shearhomo-mixer. Then, hypromellose and talc are added and dispersed with ahomo-mixer and propeller mixer at ambient temperature to produce the“Coating Suspension”.k) The tablet cores are coated with the “Coating Suspension” to thetarget weight gain to produce the “Film-coated Tablets”. The “CoatingSuspension” should be stirred again before use and kept stirring slowlyduring the coating (spraying) process.

Narrative More Specific Description of an Alternative ManufacturingProcess for the Mono-Layer Tablets:

-   a) Metformin HCl is sieved using a screen with a mesh size of 0.5 to    1 mm before weighing.-   b) L-arginine and copolyvidon are dissolved in purified water at    ambient temperature with a propeller mixer to produce the    “Granulation Liquid”-   c) Metformin HCl and corn starch are heated in a chamber of    fluid-bed granulator at 70-80° C. for more than 15 min until the    product temperature reaches 60° C.-   d) BI 1356 is added into the container, then blended with metformin    HCl and corn starch in the fluid-bed granulator.-   e) The “Granulation Liquid” is sprayed into the mixture for    fluid-bed granulating under dry condition to avoid blocking during    granulation.-   f) At the end of spraying, the resultant granulate is dried at    70-80° C. until the desired LOD value (i.e. 1-2%), in case the LOD    is more than 2%.-   g) The granulate is sieved using a screen with a mesh size of 0.5 to    1.0 mm.-   h) The sieved granulate and colloidal anhydrous silica (Aerosil 200)    are blended with a suitable blender. Aerosil 200 should be sieved    with a 0.5 mm-screen before use.-   i) Magnesium stearate passed through a 0.5 mm sieve and added into    the granulate. Subsequently the “Final Blend” is produced by final    blending in the blender.-   j) The “Final Blend” is compressed into tablets with a rotary press.-   k) Hypromellose and propylene glycol are dissolved in purified water    with a propeller mixer. Talc, titanium dioxide, and iron oxide    (yellow, or yellow and red) are dispersed in purified water with a    homo-mixer. The suspension is added into the hypromellose solution,    then mixed with a propeller mixer at ambient temperature to produce    the “Coating Suspension”.-   l) The tablet cores are coated with the “Coating Suspension” to the    target weight gain to produce the “Film-coated Tablets”. The    “Coating Suspension” should be stirred again before use and kept    stirring slowly during the coating (spraying) process.

2. Bi-Layer Tablet

The composition of bi-layer tablets for a DPP-4 inhibitor of thisinvention (BI 1356)+metformin HCl FDC (Film-coated Tablets) is shown inTable 2.

TABLE 2 Composition of BI 1356 + Metformin HCl FDC Bi-layer Tablets DoseStrength (BI 1356/metformin HCl), mg 2.5/500 2.5/850 2.5/1000 Ingredient[mg] [%] [mg] [%] [mg] [%] BI 1356-portion: (450)    (100)    (450)   (100)    (450)    (100)    BI 1356 2.50  0.556 2.50  0.556 2.50  0.556L-Arginine 2.50  0.556 2.50  0.556 2.50  0.556 D-mannitol 334.75  74.39 334.75  74.39  334.75  74.39  Pregelatinized starch 45.00  10.00  45.00 10.00  45.00  10.00  Corn starch 45.00  10.00  45.00  10.00  45.00 10.00  Copovidone 13.50  3.00 13.50  3.00 13.50  3.00 Magnesium stearate6.75 1.50 6.75 1.50 6.75 1.50 Metformin HCl-portion: (570)    (100)   (969)    (100)    (1140)     (100)    Metformin Hydrochloride 500.0  87.72  850.00  87.72  1000.00   87.72  Corn starch 15.00  2.63 25.50 2.63 30.00  2.63 Copovidone 47.50  8.33 80.57  8.33 95.00  8.33Colloidal Anhydrous Silica 2.50 0.44 4.25 0.44 5.00 0.44 Magnesiumstearate 5.00 0.88 8.50 0.88 10.00  0.88 Total Mass (tablet core)1020     100.00  1419     100.00  1590     100.00  Hypromellose (5 mPa *s) 8.00 50.00  9.50 50.00  11.00  50.00  Propylene glycol 0.80 5.00 0.955.00 1.10 5.00 Talc 2.96 18.50   3.515 18.50  4.07 18.50  Titaniumdioxide 4.00 25.00  4.75 25.00  5.50 25.00  Iron oxide, yellow 0.20 1.25 0.2375 1.25  0.275 1.25 Iron oxide, red 0.04 0.25  0.0475 0.25  0.0550.25 Total Mass (film-coat) 16.00  100.00  19.00  100.00  22.00  100.00 Total Mass (coated tablet) 1036     100.00  1438     100.00  1612    100.00 

Manufacturing Procedure (Bi-Layer Tablets):

DPP-4 inhibitor of this invention (e.g. BI 1356)+metformin HCl FDCbi-layer tablets are produced by a high-shear wet granulation process(for DPP-4 inhibitor-granulate), a fluid-bed granulation process (formetformin HCl-granulate), and bi-layer tableting process with amulti-layer rotary press.

DPP-4 Inhibitor-Granulate:

By using a high-shear granulator the active DPP-4 inhibitor ingredientis pre-mixed with the diluents D-mannitol and pregelatinized starch. Themixture is moistened with granulating liquid, containing purified waterand copovidone as a binder. After further mixing, drying and sieving,the dried granulate is blended with magnesium stearate as a lubricant.

Narrative more specific description of the manufacturing process for theBI 1356-granulate:

-   a. Copovidone and L-arginine are dissolved in purified water at    ambient temperature to produce the Granulation Liquid.-   b. BI 1356, mannitol and pregelatinized starch are blended in a    suitable mixer, to produce the Pre-Mix.-   c. The Pre-mix is moistened with the Granulation Liquid and    subsequently granulated.-   d. The moist granulate is sieved through a suitable sieve.-   e. The granulate is dried at about 50° C. (maximum 60° C.) in a    suitable dryer until the desired loss on drying value is obtained.-   f. The dried granulate is sieved through a sieve with a mesh size of    1.0 mm.-   g. Magnesium stearate is passed through a 1.0 mm sieve and added to    the granulate. Subsequently the “Final Blend A” is produced by final    blending in a suitable blender.

Metformin HCl-Granulate:

Metformin HCl and corn starch are pre-treated by heating in a chamber offluid-bed granulator to remove excessive HCl and/or impurity products.After the pre-treatment of metformin HCl and corn starch, fluid-bedgranulation is conducted by spraying of “Granulation Liquid” composed ofcopolyvidon (Kollidon VA64) and purified water. After finishing offluid-bed granulation, the granulate is sieved with a suitable screen.The sieved granulate is blended with colloidal anhydrous silica (Aerosil200) and magnesium stearate as a lubricant.

Narrative More Specific Description of the Manufacturing Process for theMetformin HCl-Granulate:

a) Metformin HCl is sieved using a screen with a mesh size of 0.5 to 1mm before weighing.b) Copolyvidon is dissolved in purified water at ambient temperaturewith a propeller mixer to produce the “Granulation Liquid”c) Metformin HCl and corn starch are heated in a chamber of fluid-bedgranulator at 70-80° C. for more than 15 min until the producttemperature reaches 60° C.d) The “Granulation Liquid” is sprayed into the mixture for fluid-bedgranulating under dry condition to avoid blocking during granulation.e) At the end of spraying, the resultant granulate is dried at 70-80° C.until the desired LOD value (i.e. 1-2%), in case the LOD is more than2%.f) The granulate is sieved using a screen with a mesh size of 0.5 to 1.0mm.g) The sieved granulate and colloidal anhydrous silica (Aerosil 200) areblended with a suitable blender. Aerosil 200 should be sieved with a 0.5mm-screen before use.h) Magnesium stearate passed through a 0.5 mm sieve and added into thegranulate. Subsequently the “Final Blend B” is produced by finalblending in the blender.

The “Final Blend A” and “Final Blend B” are compressed into bi-layertablets using a multi-layer rotary press. The tablet cores may befilm-coated by an aqueous film-coating suspension, containinghypromellose as film-forming agent, propylene glycol as plasticizer,talc as glidant and the pigments yellow iron oxide and/or red iron oxideand titanium dioxide.

Narrative More Specific Description of the Manufacturing Process for theFilm-Coating:

a) Hypromellose and propylene glycol are dissolved in purified waterwith a propeller mixer. Talc, titanium dioxide, and iron oxide (yellow,red or yellow and red) are dispersed in purified water with ahomo-mixer. The suspension is added into the hypromellose solution, thenmixed with a propeller mixer at ambient temperature to produce the“Coating Suspension”.

b) The tablet cores are coated with the “Coating Suspension” to thetarget weight gain to produce the “Film-coated Tablets”. The “CoatingSuspension” should be stirred again before use and kept stirring slowlyduring the coating (spraying) process.

3. Tablet-in-Tablet or Bull's Eye Tablet

The composition of Tablet-in-Tablet or Bull's eye tablets for a DPP-4inhibitor of this invention (BI 1356)+metformin HCl FDC (Film-coatedTablets) is shown in Table 3.

TABLE 3 Composition of BI 1356 + Metformin HCl FDC Tablet-in-Tablet orBull's Eye Tablets Dose Strength (BI 1356/metformin HCl), mg 2.5/5002.5/850 2.5/1000 Ingredient [mg] [%] [mg] [%] [mg] [%] BI 1356-portion:(45)    (100)    (45)    (100)    (45)    (100)    BI 1356 2.50 5.562.50 5.56 2.50 5.56 L-Arginine 1.00 2.22 1.00 2.22 1.00 2.22 D-mannitol30.475 67.72  30.475 67.72  30.475 67.72  Pregelatinized starch 4.5010.00  4.50 10.00  4.50 10.00  Corn starch 4.50 10.00  4.50 10.00  4.5010.00  Copovidone  1.350 3.00  1.350 3.00 1.35 3.00 Magnesium stearate 0.675 1.50  0.675 1.50 6.75 1.50 Metformin HCl-portion: (570)   (100)    (969)    (100)    (1140)     (100)    Metformin Hydrochloride500.0  87.72  850.00  87.72  1000.00   87.72  Corn starch 15.00  2.6325.50  2.63 30.00  2.63 Copovidone 47.50  8.33 80.57  8.33 95.00  8.33Colloidal Anhydrous Silica 2.50 0.44 4.25 0.44 5.00 0.44 Magnesiumstearate 5.00 0.88 8.50 0.88 10.00  0.88 Total Mass (tablet core) 615   100.00  1014     100.00  1185     100.00  Hypromellose (5 mPa * s) 6.0050.00  8.00 50.00  9.00 50.00  Propylene glycol 0.60 5.00 0.80 5.00 0.905.00 Talc 2.22 18.50  2.96 18.50  3.33 18.50  Titanium dioxide 3.0025.00  4.00 25.00  4.50 25.00  Iron oxide, yellow 0.15 1.25 0.20 1.25 0.225 1.25 Iron oxide, red 0.03 0.25 0.04 0.25  0.045 0.25 Total Mass(film-coat) 12.00  100.00  16.00  100.00  18.00  100.00  Total Mass(coated tablet) 627    100.00  1030     100.00  1203     100.00 

Manufacturing Procedure (Tablet-in-Tablet or Bull's Eye Tablet):

DPP-4 inhibitor of this invention (e.g. BI 1356)+metformin HCl FDCTablet-in-Tablet or Bull's eye tablets are produced by a high-shear wetgranulation process (for DPP-4 inhibitor-granulate), a rotary press (forDPP-4 inhibitor core-tablet), a fluid-bed granulation process (formetformin HCl-granulate), and press-coating process with a press-coater.

DPP-4 Inhibitor Core-Tablet:

By using a high-shear granulator the active DPP-4 inhibitor ingredientis pre-mixed with the diluents D-mannitol and pregelatinized starch. Themixture is moistened with granulating liquid, containing purified waterand copovidone as a binder. After further mixing, drying and sieving,the dried granulate is blended with magnesium stearate as a lubricant.

Narrative more specific description of the manufacturing process for theBI 1356 core-tablets:

-   a. Copovidone and L-arginine are dissolved in purified water at    ambient temperature to produce the Granulation Liquid.-   b. BI 1356, mannitol and pregelatinized starch are blended in a    suitable mixer, to produce the Pre-Mix.-   c. The Pre-mix is moistened with the Granulation Liquid and    subsequently granulated.-   d. The moist granulate is sieved through a suitable sieve.-   e. The granulate is dried at about 50° C. (maximum 60° C.) in a    suitable dryer until the desired loss on drying value is obtained.-   f. The dried granulate is sieved through a sieve with a mesh size of    1.0 mm.-   g. Magnesium stearate is passed through a 1.0 mm sieve and added to    the granulate. Subsequently the “Final Blend” is produced by final    blending in a suitable blender.-   h. “Final Blend” is compressed into “BI 1356 core-tablets” with a    rotary press.

Metformin HCl-Granulate:

Metformin HCl and corn starch are pre-treated by heating in a chamber offluid-bed granulator to remove excessive HCl and/or impurity products.After the pre-treatment of metformin HCl and corn starch, fluid-bedgranulation is conducted by spraying of “Granulation Liquid” composed ofcopolyvidon (Kollidon VA64) and purified water. After finishing offluid-bed granulation, the granulate is sieved with a suitable screen.The sieved granulate is blended with colloidal anhydrous silica (Aerosil200) and magnesium stearate as a lubricant.

Narrative More Specific Description of the Manufacturing Process for theMetformin HCl-Granulate:

a) Metformin HCl is sieved using a screen with a mesh size of 0.5 to 1mm before weighing.b) Copolyvidon is dissolved in purified water at ambient temperaturewith a propeller mixer to produce the “Granulation Liquid”c) Metformin HCl and corn starch are heated in a chamber of fluid-bedgranulator at 70-80° C. for more than 15 min until the producttemperature reaches 60° C.d) The “Granulation Liquid” is sprayed into the mixture for fluid-bedgranulating under dry condition to avoid blocking during granulation.e) At the end of spraying, the resultant granulate is dried at 70-80° C.until the desired LOD value (i.e. 1-2%), in case the LOD is more than2%.f) The granulate is sieved using a screen with a mesh size of 0.5 to 1.0mm.g) The sieved granulate and colloidal anhydrous silica (Aerosil 200) areblended with a suitable blender. Aerosil 200 should be sieved with a 0.5mm-screen before use.h) Magnesium stearate passed through a 0.5 mm sieve and added into thegranulate. Subsequently “Metformin HCl-granulate” (Final Blend) isproduced by final blending in the blender.

The “DPP-4 inhibitor core-tablets” and “Metformin HCl-granulate” arecompressed into Tablet-in-Tablet or Bull's eye tablets using apress-coater. The difference between the Tablet-in-Tablet and Bull's eyetablet is the position of the core tablet.

Narrative More Specific Description of the Manufacturing Process for theTablet-in-Tablet:

a) Fill a half of Metformin HCl-granulate in a die.b) Place a BI 1356 core-tablet on the surface of MetforminHCl-granulate.c) Cover the core-tablet with second half of Metformin HCl-granulate,then compressed into the tablet (Tablet-in-Tablet).

Narrative More Specific Description of the Manufacturing Process for theBull's Eye Tablets:

a) Fill Metformin HCl-granulate in a die.

b) Place the BI 1356 core-tablet on the Metformin HCl-granulate in thedie, then compressed into the tablet (Bull's eye tablet).

The tablets may be film-coated by an aqueous film-coating suspension,containing hypromellose as film-forming agent, propylene glycol asplasticizer, talc as glidant and the pigments yellow iron oxide and/orred iron oxide and titanium dioxide.

Narrative More Specific Description of the Manufacturing Process for theFilm-Coating:

a) Hypromellose and propylene glycol are dissolved in purified waterwith a propeller mixer. Talc, titanium dioxide, and iron oxide (yellow,red or yellow and red) are dispersed in purified water with ahomo-mixer. The suspension is added into the hypromellose solution, thenmixed with a propeller mixer at ambient temperature to produce the“Coating Suspension”.b) The tablet cores are coated with the “Coating Suspension” to thetarget weight gain to produce the “Film-coated Tablets”. The “CoatingSuspension” should be stirred again before use and kept stirring slowlyduring the coating (spraying) process.

4. DPP-4 Inhibitor Drug Layering on Metformin HCl Tablet (Film-Coatingfor Drug-Loading)

The composition of a DPP-4 inhibitor of this invention (BI1356)+metformin HCl FDC (Film-coated Tablets) which are prepared by drugloading by film-coating on the Metformin HCl Tablet is shown in Table 4.

TABLE 4 Composition of BI 1356 + Metformin HCl FDC BI 1356-Coating onMetformin HCl Tablet Dose Strength (BI 1356/metformin HCl), mg 2.5/5002.5/850 2.5/1000 Ingredient [mg] [%] [mg] [%] [mg] [%] MetforminHCl-portion: (570)    (100)    (969)    (100)    (1140)     (100)   Metformin Hydrochloride 500.0   87.72  850.0   87.72  1000.0   87.72 Corn starch 15.0  2.63 25.5  2.63 30.0  2.63 Copovidone 47.5  8.3380.57  8.33 95.0  8.33 Colloidal Anhydrous Silica 2.5  0.44 4.25 0.445.0  0.44 Magnesium stearate 5.0  0.88 8.5  0.88 10.0  0.88 Total Mass(tablet core) 570    100.00  969    100.00  1140     100.00  Seal-coat(seal-coating): (12)    (100)    (16)    (100)    (18)    (100)   Hypromellose (5 mPa * s) 6.00 50.00  8.00 50.00  9.00 50.00  Propyleneglycol 0.60 5.00 0.80 5.00 0.90 5.00 Talc 2.22 18.50  2.96 18.50  3.3318.50  Titanium dioxide 3.00 25.00  4.00 25.00  4.50 25.00  Iron oxide,yellow 0.15 1.25 0.20 1.25  0.225 1.25 Iron oxide, red 0.03 0.25 0.040.25  0.045 0.25 Drug-layer (drug-loading): (25)    (100)    (25)   (100)    (25)    (100)    BI 1356 2.50 10.00  2.50 10.00  2.50 10.00 L-Arginine 2.50 10.00  2.50 10.00  2.50 10.00  Hypromellose (5 mPa * s)18.00  72.00  18.00  72.00  18.00  72.00  Propylene glycol 2.00 8.002.00 8.00 2.00 8.00 Over-coat (over-coating): (12)    (100)    (16)   (100)    (18)    (100)    Hypromellose (5 mPa * s) 6.00 50.00  8.0050.00  9.00 50.00  Propylene glycol 0.60 5.00 0.80 5.00 0.90 5.00 Talc2.22 18.50  2.96 18.50  3.33 18.50  Titanium dioxide 3.00 25.00  4.0025.00  4.50 25.00  Iron oxide, yellow 0.15 1.25 0.20 1.25  0.225 1.25Iron oxide, red 0.03 0.25 0.04 0.25  0.045 0.25 Total Mass (film-coat)49    100.00  57    100.00  61    100.00  Total Mass (coated tablet)619    100.00  1026     100.00  1201     100.00 

Manufacturing Procedure (DPP-4 Inhibitor-Drug Layering by Film-Coatingon Metformin HCl Tablet):

DPP-4 inhibitor (e.g. BI 1356)+metformin HCl FDC with drug coating isproduced by a fluid-bed granulation process, a conventional tabletingprocess, and film-coating process with three steps: seal-coating,drug-loading and over-coating. The over-coating may be able to beskipped by combining with the drug-loading, if the stability isacceptable.

Metformin HCl Tablets:

Metformin HCl and corn starch are pre-treated by heating in a chamber offluid-bed granulator to remove excessive HCl and/or impurity products.After the pre-treatment of metformin HCl and corn starch, fluid-bedgranulation is conducted by spraying of “Granulation Liquid” composed ofcopolyvidon (Kollidon VA64) and purified water. After finishing offluid-bed granulation, the granulate is sieved with a suitable screen.The sieved granulate is blended with colloidal anhydrous silica (Aerosil200) and magnesium stearate as a lubricant. The final blend iscompressed into the tablets with a conventional rotary press.

Narrative More Specific Description of the Manufacturing Process for theMetformin HCl-Granulate:

a) Metformin HCl is sieved using a screen with a mesh size of 0.5 to 1mm before weighing.b) Copolyvidon is dissolved in purified water at ambient temperaturewith a propeller mixer to produce the “Granulation Liquid”c) Metformin HCl and corn starch are heated in a chamber of fluid-bedgranulator at 70-80° C. for more than 15 min until the producttemperature reaches 60° C.d) The “Granulation Liquid” is sprayed into the mixture for fluid-bedgranulating under dry condition to avoid blocking during granulation.e) At the end of spraying, the resultant granulate is dried at 70-80° C.until the desired LOD value (i.e. 1-2%), in case the LOD is more than2%.f) The granulate is sieved using a screen with a mesh size of 0.5 to 1.0mm.g) The sieved granulate and colloidal anhydrous silica (Aerosil 200) areblended with a suitable blender. Aerosil 200 should be sieved with a 0.5mm-screen before use.h) Magnesium stearate passed through a 0.5 mm sieve and added into thegranulate. Subsequently “Final Blend” is produced by final blending inthe blender.i) The “Final Blend” is compressed into the tablets with a conventionalrotary press.

Film-Coating:

The tablets are film-coated by (1) seal-coating: by an aqueousfilm-coating suspension, containing hypromellose as film-forming agent,propylene glycol as plasticizer, talc as glidant and the pigments yellowiron oxide and/or red iron oxide and titanium dioxide, (2) drug-loading:by an aqueous film-coating suspension, containing hypromellose asfilm-forming agent, propylene glycol as plasticizer, BI 1356 as drugsubstance, and L-arginine as stabilizer, and (3) over-coating: by anaqueous film-coating suspension, containing hypromellose as film-formingagent, propylene glycol as plasticizer, talc as glidant and the pigmentsyellow iron oxide and/or red iron oxide and titanium dioxide,

Narrative More Specific Description of the Manufacturing Process for theFilm-Coating with a Coating Machine:

a) Hypromellose and propylene glycol are dissolved in purified waterwith a propeller mixer. Talc, titanium dioxide, and iron oxide (yellow,red or yellow and red) are dispersed in purified water with ahomo-mixer. The suspension is added into the hypromellose solution, thenmixed with a propeller mixer at ambient temperature to produce the“Coating Suspension” for “seal-coating” and “over-coating”.b) Hypromellose, propylene glycol and L-arginine are dissolved inpurified water with a propeller mixer. BI 1356 (active drug) is addedinto the hypromellose solution, then dispersed with a propeller mixer atambient temperature to produce the “Drug Suspension” for “drug-loading”.c) The Metformin HCl tablets are coated with the “Coating Suspension” tothe target weight gain to form the “seal-coat”. The “Coating Suspension”should be stirred again before use and kept stirring slowly during thecoating (spraying) process.d) Following the seal-coating, the “Drug Suspension” is applied to thesurface of the Metformin HCl tablets to form the “drug layer” (drugloading). The “Drug Suspension” should be stirred again before use andkept stirring slowly during the coating (spraying) process. The coatingend point can be determined by available PAT (Process AnalysisTechnology).e) After drug loading the “Coating Suspension” is applied to the BI 1356drug-loaded tablets to form the “over-coat” and to produce the“Film-coated Tablets”. The “Coating Suspension” should be stirred againbefore use and kept stirring slowly during the coating (spraying)process.

Product Description:

The product description of BI 1356+Metformin HCl FDC mono-layer tablets(tablet core and film-coated tablets) is shown in Table 8 and Table 9,respectively.

TABLE 8 Product Description of BI 1356 + Metformin HCl FDC Mono-layerTablets (Tablet Core) Dose Strength (BI 1356/ metformin HCl), mg Items2.5/500 2.5/850 2.5/1000 Tablet shape Oval, Oval, Oval, biconvexbiconvex biconvex Tablet size [mm] 16.2 × 8.5 19.1 × 9.3 21.0 × 9.6Color white Weight 590 1000 1180 Thickness [mm], (Mean) Approx. 5.8Approx. 7.3 Approx. 7.6 Crushing strength [N], (Mean) ≧100, ≧150, ≧150,Approx. 140 Approx. 190 Approx. 200 Disintegration time [min] ≦15   ≦15 ≦15 Friability [%]  ≦0.5   ≦0.5   ≦0.5

TABLE 9 Product Description of BI 1356 + Metformin HCl FDC Mono-layerTablets (Coated) Dose Strength (BI 1356/ metformin HCl), mg Items2.5/500 2.5/850 2.5/1000 Color light yellow light orange light redWeight 602 1016 1198 Thickness [mm], (Mean) Approx. 5.9 Approx. 7.4Approx. 7.7 Crushing strength [N] (Mean) ≧100, ≧150, ≧150, Approx. 180Approx. 240 Approx. 250 Disintegration time [min] ≦15   ≦15  ≦15

Stability Data:

Stability data of BI 1356+Metformin HCl FDC mono-layer tablets (tabletcore) with or without L-arginine is shown in the following tables (over2 weeks, 1 month and 3 months):

2.5+500 mg tablets+12.5 mg arginine:

60° C. glass bottle Test parameter Initial 2 W 1 M 3 M Degradation BI1356 (%) <0.2 <0.2 <0.2 <0.2 Total

2.5+500 mg tablets+0 mg arginine:

60° C. glass bottle Test parameter Initial 2 W 1 M 3 M Degradation BI1356 (%) <0.2 1.1 2.9 8.5 Total

2.5+1000 mg tablets+25 mg arginine:

60° C. glass bottle Test parameter Initial 2 W 1 M 3 M Degradation BI1356 (%) <0.2 <0.2 <0.2 0.2 Total

2.5+1000 mg tablets+0 mg arginine:

60° C. glass bottle Test parameter Initial 2 W 1 M 3 M Degradation BI1356 (%) <0.2 1.9 4.7 13.6 Total

1. A pharmaceutical composition comprising or made from: (a)1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinein a dosage of 2.5 mg or 5 mg, (b) metformin hydrochloride, (c) one ormore pharmaceutical excipients, and (d) a basic amino acid having anintramolecular amino group and alkaline characteristics, wherein thepharmaceutical composition is a tablet comprising a film-coat; andwherein the pharmaceutical composition comprises the following amounts(% by weight of total coated tablet mass): 0.1-0.5% of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine,and 47-85% of metformin hydrochloride.
 2. The pharmaceutical compositionaccording to claim 1, wherein1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthineis stabilized against chemical degradation.
 3. The pharmaceuticalcomposition according to claim 1, wherein the basic amino acid having anintramolecular amino group and alkaline characteristics is selected fromL-arginine, L-lysine and L-histidine.
 4. The pharmaceutical compositionaccording to claim 1, wherein1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthineis present in a dosage strength of 5 mg.
 5. The pharmaceuticalcomposition according to claim 1, wherein1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthineis present in a dosage strength of 2.5 mg.
 6. The pharmaceuticalcomposition according to claim 1, wherein metformin hydrochloride ispresent in a dosage range from about 100 mg to about 1500 mg.
 7. Thepharmaceutical composition according to claim 6, wherein metforminhydrochloride is present in a dosage strength of 250, 500, 625, 750,850, or 1000 mg.
 8. The pharmaceutical composition according to claim 6,wherein metformin hydrochloride is present in a dosage strength of 500mg, 850 mg, or 1000 mg.
 9. The pharmaceutical composition according toclaim 1, wherein the basic amino acid having an intramolecular aminogroup and alkaline characteristics is L-arginine.
 10. The pharmaceuticalcomposition according to claim 9, wherein L-arginine is present fromabout 1 mg to about 25 mg.
 11. The pharmaceutical composition accordingto claim 9, wherein L-arginine is present from about 1 mg to about 50mg.
 12. The pharmaceutical composition according to claim 9, wherein1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthineand L-arginine are present in a weight ratio from about 1:20 to about10:1.
 13. The pharmaceutical composition according to claim 9, wherein1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthineand L-arginine are present in a weight ratio from about 1:15 to about10:1.
 14. The pharmaceutical composition according to claim 9, wherein1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthineand L-arginine are present in a weight ratio from about 1:10 to about10:1.
 15. The pharmaceutical composition according to claim 1, whereinthe excipients are selected from the group consisting of one or morefillers, a binder, a lubricant, and a glidant.
 16. The pharmaceuticalcomposition according to claim 1, comprising copovidone as binder. 17.The pharmaceutical composition according to claim 16, further comprisingone or more of the following: the filler corn starch, the lubricantmagnesium stearate, and the glidant colloidal anhydrous silica.
 18. Thepharmaceutical composition according to claim 1, wherein the tablet is amono-layer tablet.
 19. The pharmaceutical composition according to claim1, wherein the film-coat comprises a film-coating agent, a plasticizer,optionally a glidant, and optionally one or more pigments.
 20. Thepharmaceutical composition according to claim 1, in which thepharmaceutical composition is a mono-layer tablet, wherein one or moreof the following applies: the percentage of metformin hydrochloride isabout 85% by weight of total tablet core, the percentage of DPP-4inhibitor is about 0.2%-0.4% by weight of total tablet core, thepercentage of L-arginine is about 2% by weight of total tablet core, thetablet crushing strength is higher than or equal 100 N, the tabletfriability is lower than or equal 0.5%, the tablet thickness is fromabout 5.7 to about 8.4 mm, the tablet core weight is from about 590 toabout 1180 mg, and the tablet disintegration time is lower than or equal15 minutes.
 21. The pharmaceutical composition according to claim 1,which is an immediate release dosage form, characterized in that in adissolution test after 45 minutes at least 75% by weight of each of theactive ingredients is dissolved.
 22. A solid pharmaceutical compositionwhich is a mono-layer tablet comprising:1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinein a dosage of 2.5 mg, metformin hydrochloride, L-arginine, and one ormore fillers and one or more binders, wherein the percentage of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthineis about 0.2%-0.4% by weight of total tablet core.
 23. The solidpharmaceutical composition according to claim 22, further comprising oneor more glidants and/or one or more lubricants.
 24. The pharmaceuticalcomposition according to claim 1 comprising the active ingredients in adosage strength of 2.5 mg of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthineand 500 mg of metformin hydrochloride.
 25. The pharmaceuticalcomposition according to claim 1 comprising the active ingredients in adosage strength of 2.5 mg of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthineand 850 mg of metformin hydrochloride.
 26. The pharmaceuticalcomposition according to claim 1 comprising the active ingredients in adosage strength of 2.5 mg of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthineand 1000 mg of metformin hydrochloride.
 27. The pharmaceuticalcomposition according to claim 1, wherein the pharmaceutical compositionfurther comprises the following amount (% by weight of total coatedtablet mass): 0.07-2.2% of L-arginine.